Multi-microdialysis analytical system to monitor acetaminophen and its pharmacokinetic interaction with A. bidentata in rat blood, forelimb extensor muscle, brain striatum, and the knee joint cavity.

Acetaminophen (APAP), or paracetamol, is one of the most widespread and commonly used non-prescription pain medication in the world, and is effective at managing wide range of pain, including headache, muscle ache, and minor arthritic pain. While the pharmacokinetics of APAP is generally understood, there is a lack of data for its transfer ratio especially into the knee. A novel multi-microdialysis model was developed to simultaneously sample from blood, forelimb extensor muscle, brain striatum, and the knee joint cavity in the same experimental subject to investigate the potential interaction between APAP and Achyranthes bidentata Blume (A. bidentata), another widely used traditional Chinese medicininal herb especially for pain in the lower extremity. Rats were pre-treated with A. bidentata extract (ABex), APAP was then administered (60 mg/kg, i.v.), dialysates then subsequently analyzed using HPLC-PDA. Our analysis demonstrated that APAP concentrations, achieved after its administration either alone or in combination with ABex (1 and 3 g/kg, q.d. gavage), could be modelled effectively with a one-compartment model. The distribution ratio (AUCorgan/AUCblood) of blood-to-muscle, blood-to-brain and blood-to-knee was 0.372 ± 0.053, 0.277 ± 0.095 and 0.191 ± 0.042, respectively after administration of APAP (60 mg/kg, i.v.). No significant difference was observed between the pharmacokinetics of APAP administered alone and in combination with ABex; and APAP concentration exceed the half maximal effective concentration (EC50) in all sampled organs for close to 3 hours with one single dose of drug administration, providing evidence for its broad-range analgesic effect.

Protective Effects of Epigallocatechin Gallate for Male Sexual Dysfunction in Streptozotocin-Induced Diabetic Rats.

Sexual dysfunction is a common problem for men with diabetes. Epigallocatechin gallate (EGCG) is known to ameliorate erectile function in aging rats. However, there has not yet been a report to evaluate its effects on diabetic male rat sexual behavior in the literature. In this study, we investigated the effects of EGCG on male sexual behavior in diabetic rats. Diabetic rats were induced by a single intraperitoneal injection of 65 mg/kg of streptozotocin. After streptozotocin injection for one week, animals were then orally treated with 40 mg/kg of EGCG or vehicle. Copulatory behavior and fasting blood glucose levels were recorded before treatment, as well as 7 and 14 days after treatment. Serum LH, testosterone, and PDE5a levels were measured by EIA assay after the last behavioral test. Data showed that diabetic rats who had diminished sexual functions demonstrated significantly increased latencies in mount, intromission, and ejaculation, as well as significant decreases in frequencies of intromission and ejaculation, compared to non-diabetic controls, indicating sexual function recovery. Lower blood glucose levels were also found in diabetic rats after EGCG treatment. Additionally, the lower LH and higher PDE5a levels in diabetic rats than controls were also noted. The findings declared that EGCG had a protective effect on male sexual behavior in diabetic rats.

Ten-years outcome analysis in patients with clinically localized prostate cancer treated by radical prostatectomy or external beam radiation therapy.

Purpose: Since there was no consensus on treatment options for localized prostate cancer, we performed a retrospective study to compare the long-term survival benefit of radiotherapy (RT) versus laparoscopic radical prostatectomy (LRP) in Taiwan. Methods: 218 patients with clinically localized prostate cancer treated between 2008 and 2017 (64 with LRP and 154 with RT) were enrolled in this study. The outcomes of RT and LRP were assessed after patients were stratified according to Gleason score, stage, and risk group. Crude survival, prostate cancer-specific survival, and metastasis-free survival were evaluated using the log-rank test. Results: The 5-year crude survival rate was 93.3% in the LRP group and 59.3% in the RT group. A significant survival benefit was found in the LRP group compared with the RT group (p = 0.004). Furthermore, significant differences were found in disease-specific survival (93.3% vs. 64.7%, p = 0.022) and metastasis-free survival (48% vs. 40.2%, p = 0.045) between the LRP and RT groups. Conclusions: Men with localized prostate cancer treated initially with LRP had a lower risk of prostate cancer-specific death and metastases compared with those treated with RT.

Preclinical Pharmacokinetics and Pharmacodynamics of Coptidis Preparation in Combination with Lovastatin in High-Fat Diet-Induced Hyperlipidemic Rats.

Lovastatin is a standard therapy for dyslipidemia. Alternatively, some ethnomedicines, such as Coptidis preparation, have been used for the treatment of dyslipidemia. Statins and complementary and alternative medicines may possess individual mechanisms of action against dyslipidemia. We hypothesize that the combination of Coptidis preparation and lovastatin may have synergistic effects for the treatment of dyslipidemia. To investigate this hypothesis, we developed a validated ultra-high-performance liquid chromatography-tandem mass spectrometry method to monitor lovastatin and its metabolites for pharmacokinetic studies in rats. This study was divided into four groups: lovastatin (10 mg/kg, p.o.) alone and lovastatin (10 mg/kg, p.o.) + Coptidis preparation (0.3, 1, or 3 g/kg, p.o.) for five consecutive days. In pharmacodynamic studies, a high-fat diet (HFD) was used to induce dyslipidemia in experimental rat models. The HFD rats were divided into four groups: treatment with HFD, HFD + lovastatin (100 mg/kg, p.o.), HFD + Coptidis preparation (1 g/kg, p.o.), and HFD + lovastatin (50 mg/kg, p.o.) + Coptidis preparation (1 g/kg, p.o.) for 28 consecutive days. The pharmacokinetic results demonstrated that Coptidis preparation significantly augmented the conversion of lovastatin into its main metabolite lovastatin acid in vivo. The pharmacodynamic results revealed that the Coptidis preparation and half-dose lovastatin group reduced the body weight, liver weight, and visceral fat in HFD rats. These findings provide constructive preclinical pharmacokinetic and pharmacodynamic applications of Coptidis preparation on the benefit of hyperlipidemia.

Non-Muscular Invasive Bladder Cancer: Re-envisioning Therapeutic Journey from Traditional to Regenerative Interventions.

Non-muscular invasive bladder cancer (NMIBC) is one of the most common cancer and major cause of economical and health burden in developed countries. Progression of NMIBC has been characterized as low-grade (Ta) and high grade (carcinoma in situ and T1). The current surgical intervention for NMIBC includes transurethral resection of bladder tumor; however, its recurrence still remains a challenge. The BCG-based immunotherapy is much effective against low-grade NMIBC. BCG increases the influx of T cells at bladder cancer site and inhibits proliferation of bladder cancer cells. The chemotherapy is another traditional approach to address NMIBC by supplementing BCG. Notwithstanding, these current therapeutic measures possess limited efficacy in controlling NMIBC, and do not provide comprehensive long-term relief. Hence, biomaterials and scaffolds seem an effective medium to deliver therapeutic agents for restructuring bladder post-treatment. The regenerative therapies such as stem cells and PRP have also been explored for possible solution to NMIBC. Based on above-mentioned approaches, we have comprehensively analyzed therapeutic journey from traditional to regenerative interventions for the treatment of NMIBC.

Low-frequency electroacupuncture at acupoints guanyuan (CV4) and zhongji (CV3) lengthen ejaculatory latency and improves sexual behavior in male rats.

Acupuncture is a key component of Traditional Chinese Medicine in which needles are inserted into specific areas in the body to stimulate certain physiological reactions of the body. Clinical research shows that acupuncture is beneficial in treating a variety of illnesses, such as erectile dysfunction. Therefore, we investigated the effect of electroacupuncture (EA) stimulation of both low- and high frequencies at Guanyuan (CV4) and Zhongji (CV3) acupoints on male copulatory behavior in sexually experienced male rats. The animals were randomly divided into four groups: control, sham EA, EA, and only acupuncture. The administered low and high EA were 2 Hz and 80 Hz, respectively, for which the respective intensities were 1.5 mA (30 min/day for 5 days) and 1.5 mA (30 min once). The only acupuncture-administered group received acupunctures at CV4 and CV3 without electrical stimulation. Following the acupuncture treatments, copulatory behavior test was conducted. Eventually, animals were sacrificed and blood samples were collected for testing the serum hormonal profile including luteinizing hormone (LH), testosterone (T), and serotonin (5-HT). Results showed that low-frequency EA-treated rats exhibited increasing intromissions and ejaculation latency compared to control, sham EA, and acupuncture groups, while high-frequency EA-treated rats displayed lower intromissions and ejaculation frequency when compared with those in controls. Furthermore, serum levels of 5-HT and LH in low-frequency EA-treated rats were higher than all the other groups. These results indicate that compared to high-frequency EA, the low-frequency EA might be efficacious in the treatment of premature ejaculation, thereby improving sexual behavior.

Neuronal nitric oxide synthase activity mediates Lycium barbarum polysaccharides-enhanced sexual performance without stimulating noncontact erection in rats.

RATIONALE: Lycium barbarum polysaccharide (LBP) is known to promote reproductive functions. However, its role in noncontact erection (NCE) of penis initiated by brain regions including medial preoptic area (MPOA) and paraventricular nucleus (PVN) regions responsible for sexual behavior has not been investigated. OBJECTIVES: Therefore, this study initially investigated the effects of LBP on male sexual function, and subsequently, the mechanistic insight was investigated through assessing the expression of neuronal nitric oxide synthase (nNOS) in the MPOA and PVN. METHODS: The adult male rats were treated with 100 mg/kg of LBP or vehicle by oral gavage. Before and after 14 days of treatment, copulatory behavior and noncontact erection (NCE) were recorded. After the last behavioral test, the brain was isolated to measure nNOS expression in the MPOA and PVN. RESULTS: Data showed that LBP treatment significantly increased both the frequencies of intromission as well as ejaculation, compared to the control group. Whereas, a reduced post-ejaculatory interval was observed compared to same group on day 0. Furthermore, the treatment led to an increased intromission ratio, inter-intromission interval, and the number of MPOA nNOS-immunoreactive cells (nNOS-ir). Additionally, a significantly positive correlation between ejaculation frequency and MPOA nNOS-ir cells was recorded. Of note, LBP treatment had no effects on NCE and PVN nNOS-ir expression. CONCLUSION: These findings suggest that LBP enhances sexual behavior through increased nNOS expression in the MPOA in male rats.

Investigation of Interactive Activity of Electro-Acupuncture on Pharmacokinetics of Sildenafil and Their Synergistic Effect on Penile Blood Flow in Rats.

Erectile dysfunction (ED) is a disorder found in males throughout the world, which negatively affects relationships with partners with advancing age. Hence, in this study, we tested a combined novel treatment of electro-acupuncture (EA) and sildenafil citrate against ED. In addition to EA therapy, the sildenafil citrate, a phosphodiesterase 5 inhibitor, is a widely recognized drug that has achieved considerable success in the treatment of ED. However, the combined effect of both the EA and sildenafil has not yet been investigated. Hence, we aimed to examine the effect of EA on the pharmacokinetics and pharmacodynamics of sildenafil in rat plasma. The pharmacokinetic parameters were determined using ultra performance liquid chromatography (UPLC) after EA and sildenafil administration (10 mg/Kg). Following this, the pharmacodynamics was studied via blood flow pattern using developing Doppler images of the lower body and penis. The pharmacokinetic studies demonstrated that sildenafil significantly increases by administration of low-frequency EA. Further, the pharmacodynamic studies using Doppler imaging revealed an elevated blood flow in rat penis compared with lower body during combined treatment of sildenafil and low-frequency EA. These data indicate a synergistic therapeutic effect of EA and sildenafil for the treatment of ED.

Robot-Assisted Laparoscopic Surgery for the Treatment of Urological Malignancy.

Minimally invasive surgery has always been the mainstay of therapeutic strategy in treatment of urological disorders. Urologic oncologic surgery is no exception in this regard and with availability of the da Vinci robotic system has favorably altered the surgical outcomes of treatment of urologic malignancies including prostatectomy, cystectomy, and partial nephrectomy. Robotic system not only makes these procedures truly minimal access but also facilitates better visualization, improved dexterity, and better outcomes in terms of surgical morbidity. In this article, we collect and review the recent articles which have studied the application of this technology and its outcomes.

Effect of minimizing tension during robotic-assisted laparoscopic radical prostatectomy on urinary function recovery.

OBJECTIVES: Although most prostatectomy studies emphasize optimal nerve-sparing dissection planes, subtle technical variation also affects functional outcomes. The impact of minimizing assistant/surgeon tension on urinary function has not been quantified. We assess urinary function after attenuating neurovascular bundle (NVB) and rhabdosphincter tension during robotic-assisted radical prostatectomy (RARP). METHODS: Retrospective study of prospectively collected data for 268 (RARP-T) versus 342 (RARP-0T) men with versus without tension on the NVB and rhabdosphincter during RARP. Outcomes compared include Expanded Prostate Cancer Index (EPIC) urinary function, estimated blood loss (EBL), operative time, and positive surgical margins (PSM). RESULTS: In unadjusted analysis, men undergoing RARP-T versus RARP-0T were older, had higher biopsy and pathologic Gleason grade, and higher preoperative prostate specific antigen (all p ≤ 0.023). Baseline urinary function was similar. Postoperatively, RARP-0T versus RARP-T was associated with higher 5-month urinary function scores (69.7 versus 64, p = 0.049). In adjusted analyses, RARP-0T versus RARP-T was associated with improved 5-month urinary function [Parameter Estimate (PE) 7.37, Standard Error (SE) 2.67, p = 0.006], while bilateral versus non-/unilateral nerve-sparing was associated with improved 12-month urinary function and continence (both p ≤ 0.035). RARP-0T versus RARP-T was associated with shorter operative times (PE 6.66, SE 1.90, p = 0.001) and higher EBL (PE 20.88, SE 6.49, p = 0.001). There were no significant differences in PSM. CONCLUSIONS: While the use of tension aids in dissection of anatomic planes, avoidance of NVB counter-traction and minimizing tension on the rhabdosphincter during apical dissection attenuates neuropraxia and leads to earlier urinary function recovery. Bilateral versus non-/unilateral nerve-sparing also improves urinary function recovery.

Robotic-assisted laparoscopic radical prostatectomy after aborted retropubic radical prostatectomy.

Robotic-assisted laparoscopic prostatectomy (RALP) has surged in popularity since US Food and Drug Administration approval in 2000. Advantages include improved visualization and increased instrument dexterity within the pelvis. Obesity and narrow pelves have been associated with increased difficulty during open retropubic radical prostatectomy (RRP), but the robotic platform theoretically allows one to perform a radical prostatectomy despite these challenges. We present an example of a RALP performed following an aborted RRP. A 49-year-old male with intermediate risk prostate cancer and body mass index of 38 kg/m(2) presented for RALP after RRP was aborted by an experienced open surgeon following incision of the endopelvic fascia due to poor visualization, a prominent pubic tubercle, and a narrow pelvis. The enhanced visualization and precision of the robotic platform allowed adequate exposure of the prostate and allowed us to proceed with an uncomplicated prostatectomy, which was not possible to perform easily via an open approach. The bladder was densely adherent to the pubis and the anterior prostatic contour and apex were difficult to develop due to a dense fibrotic reaction from the previous endopelvic fascia incision. However, we were able to successfully complete RALP with subtle technical modifications. Estimated blood loss was 160 mL and operating time was 145 min. The patient's pathology was significant for a positive peri-prostatic lymph node and he has been referred to radiation oncology for adjuvant radiotherapy and androgen deprivation therapy. At 3 months follow-up he had a prostate-specific antigen level of 0.06 ng/mL, partial erections, and mild urinary incontinence requiring one pad per day. Superior intracorporeal laparoscopic visualization and improved instrument dexterity afforded by the robotic surgical platform may make RALP the preferred approach in obese men or men with difficult pelvic anatomy who are deemed poor RRP candidates.

Stepwise approach for nerve sparing without countertraction during robot-assisted radical prostatectomy: technique and outcomes.

BACKGROUND: Although subtle technical variation affects potency preservation during robot-assisted laparoscopic radical prostatectomy (RARP), most prostatectomy studies focus on achieving the optimal anatomic nerve-sparing dissection plane. However, the impact of active assistant/surgeon neurovascular bundle (NVB) countertraction on sexual function outcomes has not been studied or quantified. OBJECTIVE: To illustrate technique and compare sexual function outcomes for nerve sparing without (NS-0C) versus with (NS-C) assistant and/or surgeon NVB countertraction. DESIGN, SETTING, AND PARTICIPANTS: This is a retrospective study of 342 NS-0C versus 268 NS-C RARP procedures performed between August 2008 and February 2011. SURGICAL PROCEDURE: RARP. MEASUREMENTS: We used the Expanded Prostate Cancer Index Composite (EPIC) sexual function and potency scores, estimated blood loss (EBL), operative time, and positive surgical margin (PSM). RESULTS AND LIMITATIONS: In unadjusted analysis, men undergoing NS-0C versus NS-C were older, had worse baseline sexual function, higher biopsy and pathologic Gleason grade, and higher preoperative prostate-specific antigen (PSA) levels (all p ≤ 0.023). However, NS-0C versus NS-C was associated with higher 5-mo sexual function scores (20 vs 10; p < 0.001), and this difference was accentuated for bilateral intrafascial nerve sparing in preoperatively potent men (35.8 vs 16.6; p < 0.001). Similarly, 5-mo potency for preoperatively potent men was better with bilateral intrafascial NS-0C versus NS-C (45.0% vs 28.4%; p = 0.039). However, no difference in sexual function or potency was observed at 12 mo. In adjusted analyses, NS-0C versus NS-C was associated with improved 5-mo sexual function (parameter estimate: 10.90; standard error: 2.16; p < 0.001) and potency (odds ratio: 1.69; 95% confidence interval, 1.01-2.83; p = 0.046). NS-0C versus NS-WC was associated with shorter operative times (p = 0.001) and higher EBL (p = 0.001); however, there were no significant differences in PSM. Limitations include the retrospective, single-surgeon study design and smaller numbers for 12-mo comparison. CONCLUSIONS: Reliance on countertraction to facilitate dissecting NVB away from the prostate leads to neuropraxia and delayed recovery of sexual function and potency. Subtle technical modification to dissect the prostate away from the NVB without countertraction enables earlier return of sexual function and potency.

The impact of prostate size, median lobe, and prior benign prostatic hyperplasia intervention on robot-assisted laparoscopic prostatectomy: technique and outcomes.

BACKGROUND: Large prostate size, median lobes, and prior benign prostatic hyperplasia (BPH) surgery may pose technical challenges during robot-assisted laparoscopic prostatectomy (RALP). OBJECTIVE: To describe technical modifications to overcome BPH sequelae and associated outcomes. DESIGN, SETTINGS, AND PARTICIPANTS: A retrospective study of prospective data on 951 RALP procedures performed from September 2005 to November 2010 was conducted. Outcomes were analyzed by prostate weight, prior BPH surgical intervention (n=59), and median lobes >1 cm (n=42). SURGICAL PROCEDURE: RALP. MEASUREMENTS: Estimated blood loss (EBL), blood transfusions, operative time, positive surgical margin (PSM), and urinary and sexual function were measured. RESULTS AND LIMITATIONS: In unadjusted analysis, men with larger prostates and median lobes experienced higher EBL (213.5 vs 176.5 ml; p<0.001 and 236.4 vs 193.3 ml; p=0.002), and larger prostates were associated with more transfusions (4 vs 1; p=0.037). Operative times were longer for men with larger prostates (164.2 vs 149.1 min; p=0.002), median lobes (185.8 vs 155.0 min; p=0.004), and prior BPH surgical interventions (170.2 vs 155.4 min; p=0.004). Men with prior BPH interventions experienced more prostate base PSM (5.1% vs 1.2%; p=0.018) but similar overall PSM. In adjusted analyses, the presence of median lobes increased both EBL (p=0.006) and operative times (p<0.001), while prior BPH interventions also prolonged operative times (p=0.014). However, prostate size did not affect EBL, PSM, or recovery of urinary or sexual function. CONCLUSIONS: Although BPH characteristics prolonged RALP procedure times and increased EBL, prostate size did not affect PSM or urinary and sexual function.

Athermal division and selective suture ligation of the dorsal vein complex during robot-assisted laparoscopic radical prostatectomy: description of technique and outcomes.

BACKGROUND: Apical dissection and control of the dorsal vein complex (DVC) affects blood loss, apical positive margins, and urinary control during robot-assisted laparoscopic radical prostatectomy (RALP). OBJECTIVE: To describe technique and outcomes for athermal DVC division followed by selective suture ligation (DVC-SSL) compared with DVC suture ligation followed by athermal division (SL-DVC). DESIGN, SETTINGS, AND PARTICIPANTS: Retrospective study of prospectively collected data from February 2008 to July 2010 for 303 SL-DVC and 240 DVC-SSL procedures. SURGICAL PROCEDURE: RALP with comparison of DVC-SSL prior to anastomosis versus early SL-DVC prior to bladder-neck dissection. MEASUREMENTS: Blood loss, transfusions, operative time, apical and overall positive margins, urine leaks, catheterization duration, and urinary control at 5 and 12 mo evaluated using 1) the Expanded Prostate Cancer Index (EPIC) urinary function scale and 2) continence defined as zero pads per day. RESULTS AND LIMITATIONS: Men who underwent DVC-SSL versus SL-DVC were older (mean: 59.9 vs 57.8 yr, p<0.001), and relatively fewer white men underwent DVC-SSL versus SL-DVC (87.5% vs 96.7%, p<0.001). Operative times were also shorter for DVC-SSL versus SL-DVC (mean: 132 vs 147 min, p<0.001). Men undergoing DVC-SSL versus SL-DVC experienced greater blood loss (mean: 184.3 vs 175.6 ml, p=0.033), and one DVC-SSL versus zero SL-DVC were transfused (p=0.442). Overall (12.2% vs 12.0%, p=1.0) and apical (1.3% vs 2.7%, p=0.361) positive surgical margins were similar for DVC-SSL versus SL-DVC. Although 5-mo postoperative urinary function (mean: 72.9 vs 55.4, p<0.001) and continence (61.4% vs 39.6%, p<0.001) were better for DVC-SSL versus SL-DVC, 12-mo urinary outcomes were similar. In adjusted analyses, DVC-SSL versus SL-DVC was associated with shorter operative times (parameter estimate [PE]±standard error [SE]: 16.84±2.56, p<0.001), and better 5-mo urinary function (PE±SE: 19.93±3.09, p<0.001) and continence (odds ratio 3.39, 95% confidence interval 2.07-5.57, p<0.001). CONCLUSIONS: DVC-SSL versus SL-DVC improves early urinary control and shortens operative times due to fewer instrument changes with late versus early DVC control.